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On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we presumed that PEPCK-M could play a role in this process by offsetting key metabolites into glycosyl moieties using alternative substrates. PEPCK-M inhibition using iPEPCK-2 promoted entosis in the absence of glucose, whereas its overexpression inhibited entosis. PEPCK-M inhibition had a direct role on total protein glycosylation as determined by Concanavalin A binding, and the specific ratio of fully glycosylated LAMP1 or E-cadherin. The content of metabolites, and the fluxes from C-glutamine label into glycolytic intermediates up to glucose-6-phosphate, and ribose- and ribulose-5-phosphate, was dependent on PEPCK-M content as measured by GC/MS. All in all, we demonstrate for the first time that protein glycosylation defects precede and initiate the entosis process and implicates PEPCK-M in this survival program to dampen the consequences of glucose deprivation. These results have broad implications to our understanding of tumor metabolism and treatment strategies., This work was supported by grants from the Spanish “Ministerio de Ciencia e Innovación” (PID2019-106640RB-I00), Generalitat de Catalunya (2017SGR106, 2017SGR204 and 2017SGR1746), the European Union (European Regional Development Fund, FEDER) to JCP. We are indebted to the “Ministerio de Educación” FPU for financial support for PH, and to the Generalitat de Catalunya FI program for partial financial support for MA. We acknowledge the skillful technical support by the Scientific and Technical Services at the University of Barcelona, Bellvitge Campus, and to the “Consorci de Serveis Universitaris de Catalunya” (CSUC) for computational facilities. We are indebted with Dr. Gabriel Pons for his help with the CRISPR/Cas9 cell line development.

Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.

Trace minerals play an important role in animal health and productivity. They are involved also in many physiological activities, and their deficiency causes a variety of pathological problems and metabolic defects, reducing consequently the animal productivity. The demand for animal products in semi-arid areas is rapidly increasing, and the supply is still below the required level, partially due to low animal productivity. Camels (Camelus dromedarius and Camelus bactrianus) are considered one of the main sources of healthy, high-quality meat and milk for human consumption within most of the countries in the semi-arid regions. Despite their efficient adaptation to their environment, camels can suffer from the growth retardation of newborns, low feed efficiency, anemia, poor fertility, poor reproduction and many other metabolic disorders. It is well known that trace mineral deficiencies and trace mineral toxicities can influence camels’ production and reproductive efficiency, as well as many aspects of their growth and metabolism. Evaluating the trace minerals status of camels and their variability is an obvious step toward improving camels’ productivity and health. Thus, the present article reviews the data regarding the status of trace minerals (copper, zinc, iron, selenium, manganese, cobalt, iodine, fluorine, molybdenum, sulfur, bromide and nickel) in camel blood and their physiological variability, with a focus on their deficiency and toxicity effects.

International audience; Le lactate a pendant de trop nombreuses années été considéré comme un simple déchet du métabolisme glycolytique, potentiellement délétère pour les organes étant donné le lien entre sa production et l’acidification du microenvironnement. Cette vision a été remise en cause par des études récentes qui placent le métabolisme du lactate au centre de l'homéostasie énergétique de l’organisme, et qui participent à sa réhabilitation en tant que métabolite majeur situé au carrefour du métabolisme glycolytique et oxydatif. De plus, cette littérature très dynamique ne cesse de mettre en lumière de nouveaux mécanismes par lesquels le lactate régule la physiologie cellulaire et notamment les processus de plasticité , en réponse aux modifications environnementales et métaboliques. Ainsi, il apparait que le lactate assure une communication métabolique inter-cellulaire et inter-tissulaire, non seulement par le transport de carbones et d’électrons entre différents compartiments, mais aussi grâce à son rôle de molécule de signalisation.

International audience; Besides structural information, magnetic resonance imaging (MRI) is crucial to reveal the presence and gradients of metabolites in organs constituted of several tissues. In plant science, such knowledge is key to better understand fruit development and metabolism. Routine methods based on fixation for cytological studies or dissection for metabolite measurements induce biases and plant sample destruction. Magnetic resonance spectroscopy imaging (MSRI) leads to one NMR spectrum per pixel while chemical exchange saturation transfer (CEST) MRI allows mapping metabolites having exchangeable protons. As both methods present different advantages and drawbacks, we compared them to map metabolites in ripe tomato fruits. We demonstrated that MRSI was difficult to interpret due to large spatial chemical shift variations while CEST MRI produced promising image mapping of the main carbohydrates and amino acids. It showed that glucose/fructose was mostly located in the locular tissue, whereas glutamate/glutamine/GABA was found inside the columella.Graphical abstract.

The requirement for Cas nucleases to recognize a specific PAM is a major restriction for genome editing. SpCas9 variants SpG and SpRY, recognizing NGN and NRN PAMs, respectively, have contributed to increase the number of editable genomic sites in cell cultures and plants. However, their use has not been demonstrated in animals. Here we study the nuclease activity of SpG and SpRY by targeting 40 sites in zebrafish and C. elegans. Delivered as mRNA-gRNA or ribonucleoprotein (RNP) complexes, SpG and SpRY were able to induce mutations in vivo, albeit at a lower rate than SpCas9 in equivalent formulations. This lower activity was overcome by optimizing mRNA-gRNA or RNP concentration, leading to mutagenesis at regions inaccessible to SpCas9. We also found that the CRISPRscan algorithm could help to predict SpG and SpRY targets with high activity in vivo. Finally, we applied SpG and SpRY to generate knock-ins by homology-directed repair. Altogether, our results expand the CRISPR-Cas targeting genomic landscape in animals., Ceron laboratory thanks the CERCA Program (Generalitat de Catalunya) for their institutional support, and Nicholas Stroustrup and Alberto Villanueva for sharing reagents and equipment, and Marta Artal and Antonio Miranda for allowing to share the information on the efficiency of the trx-1 and usp-48 endogenous reporters generation. We thank Erik Jorgensen for sharing the EG9615 strain. We thank Jordan Ward for hosting J.C. at the UCSC where cki-1 tagging was performed. This study at Cerón Lab has been funded by Ministerio de Ciencia, Innovación y Universidades, which is part of Agencia Estatal de Investigación (AEI), through the Retos grant, number PID2020-114986RB-100. This work was also supported by Ramon y Cajal (RyC-2017-23041) and MDM-2016-0687 programs (Spanish Ministerio de Ciencia, Innovación y Universidades), Universidad Pablo de Olavide (UPO) Research and the Springboard programs from UPO and CABD, respectively and has been co-funded by the Fondo Europeo de Desarrollo Regional (FEDER) and Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucía, within the operative program FEDER Andalucía 2014-2020 (01 - Refuerzo de la investigación, el desarrollo tecnológico y la innovación, grant P20_00866) (M.A.M.-M.). The Moreno-Mateos lab is supported by PGC2018-097260-B-I00 grant from Spanish Ministerio de Ciencia, Innovación y Universidades and European Union. The CABD is an institution funded by Pablo de Olavide University, Consejo Superior de Investigaciones Científicas (CSIC), and Junta de Andalucía. C.S.-B. was a recipient of the Ayudas Puente Predoctorales (Universidad Pablo de Olavide, V Plan Propio de Investigación y transferencia). J.V. had an INPhINIT PhD fellowship from “la Caixa” Foundation (LCF/BQ/IN17/11620065) co-funded by Marie Skłodowska-Curie grant agreement no. 713673. D.B. is a predoctoral fellow of the CONACYT “Becas al Extranjero” Program of Mexico. D.K. has an FI AGAUR fellowship (2018FI_B1_00511) from Generalitat de Catalunya. A.J.G. and B.P.K. acknowledge support from National Institutes of Health (NIH) R00 CA218870 and NIH P01 HL142494 (B.P.K.) and 5R35GM122580-05 (A.J.G.).

Le mélanome est caractérisé par un remodelage métabolique important, participant à la métastase et à la résistance aux traitements. Les coactivateurs 1 du récepteur activé par le proliférateur du peroxisome (PPARγ), ou PGC-1s, constituent une famille de coactivateurs qui potentialisent la transcription de gènes du métabolisme et de la biogenèse mitochondriale, participant ainsi à la reprogrammation métabolique des cellules cancéreuses. Les différents cancers de la peau expriment des niveaux variables de PGC-1s et les tumeurs qui expriment fortement les PGC-1s présentent un profil pro-inflammatoire et immunosuppresseur favorisant l’évasion immunitaire. Ceci suggère un rôle des PGC-1s dans la réponse à l’immunothérapie. Nous montrons d’abord que la déplétion en PGC-1β diminue la prolifération de lignées cellulaires de mélanome en plus d’induire l’expression de cytokines pro-inflammatoires et de transcrits immunosuppresseurs. À ce jour, les mécanismes permettant de réguler l’expression et l’activité des PGC-1s demeurent inconnus. Nous montrons que différents stress cellulaires affectant des procédés métaboliques, épigénétiques ou la traduction diminuent l’expression des PGC-1s et la viabilité de lignées cellulaires de mélanome. Nous montrons également un mécanisme de régulation de PGC-1β par une protéine de liaison à l’ARN soutenant le rôle de PGC-1β dans la réponse à différents stress et la survie des cellules de mélanome. Cette régulation serait importante pour l’immunosuppression du mélanome et dicterait la réponse à l’immunothérapie. En conclusion, ces travaux illustrent bien le rôle de PGC-1β dans la reprogrammation métabolique et la réponse au stress du mélanome, ces processus pouvant influencer l’inflammation et l’immunosuppression du microenvironnement afin d’assurer la progression tumorale., Melanoma is characterized by a significant metabolic remodeling, which contributes to metastasis and treatment resistance. Peroxisome proliferator-activated receptor gamma (PPARγ) coactivators 1, or PGC-1s, are a family of coactivators that potentiate the transcription of genes involved metabolism and mitochondrial biogenesis, thus participating in the metabolic reprogramming of cancer cells. Different skin cancers express varying levels of PGC-1s and tumors that strongly express PGC-1s exhibit a proinflammatory and immunosuppressive profile that favors immune evasion. This suggests that PGC-1s play a role in melanoma response to immunotherapy. We first show that PGC-1β knockdown decreases the proliferation of melanoma cell lines. Moreover, it induces the expression of proinflammatory cytokines and immunosuppressive transcripts. To date, the mechanisms that regulate the expression and activity of PGC-1s remain unknown. We show that different cellular stresses affecting metabolic and epigenetic processes or translation decrease PGC-1s expression and the viability of melanoma cell lines. We also show a mechanism of regulation of PGC-1β by an RNA-binding protein enhencing the role of PGC-1β in the response to different stresses and the survival of melanoma cells. This regulation could contribute to melanoma immunosuppression and determine the tumor’s response to immunotherapy. In conclusion, this work illustrates well the role of PGC-1β in melanoma metabolic reprogramming and stress response, processes that regulate inflammation and create an immunosuppressive tumor microenvironment in order to ensure tumor progression.

[eng] Leukaemia is one of the types of cancer where treatment resistance is prevalent. Better understanding of leukemic cells metabolism opens possibilities for new therapeutic strategies and better prognosis stratification. Leukaemia arises from many different genetic alterations, that affect distinct cellular processes, all driving leukemogenesis. Many of these result in a phenotype that grants metabolic advantages amidst the hypoxic conditions of the haematopoietic niche of the bone marrow, the point of origin of all types of this cancer. In order to understand the metabolic reprogramming that grants these advantages, we performed metabolic characterization in vitro of cell lines of acute monocytic leukaemia (THP1) and chronic myeloid leukaemia (HAP1), with focus on the role of Transketolase-like 1 (TKTL1) and ten-to-eleven Methylcytosine dioxygenase 2 (TET2), respectively, on both normoxic and hypoxic experimental settings. We revealed that TKTL1 is a key enzyme in the metabolic reprogramming of the hypoxia adaptation, driving proliferation, higher glycolytic rates, higher glutamine consumption and subsequent glutamate production. Our results also showed the altered metabolism of many amino acids and biogenic amines, that grant more substrates for nucleotides synthesis, higher stress tolerance and manipulation of the immune response of the microenvironment. It also highlighted the vulnerabilities that arise from focusing on targeting TKTL1 for therapy and possible secondary targetable metabolic pathways for future therapies. Additionally, we demonstrated the effects of the loss of TET2 in the leukemic cells through a tracer-based metabolomics approach, showing how its mutation primes the cells to shift their metabolism at a higher cost for their ROS homeostasis, a known hallmark of cancer which increases the risk of more mutations occurring due to genomic instability. This allowed us to create a metabolic map of the changes induced by the loss of TET2, as a blueprint for new therapeutic venues in leukaemias that have this mutational hit. Together, the thesis presented here contributes to the knowledge of the mechanisms underlying metabolic reprogramming of leukaemia according to specific mutational genotypes and how they open new possible therapies for patients that develop resistance.

Introduction : Il est connu que la cascade cellulaire impliquant le récepteur scavenger CD36 et le récepteur nucléaire PPAR a des conséquences bénéfiques sur le métabolisme gluco-lipidique. En particulier, les effets sur l’activité mitochondriale, le processus d’oxydation des acides gras, et le retour hépatique du cholestérol supporte l'utilisation de modulateurs de la cascade CD36-PPAR comme approches potentielles pour les pathologies métaboliques. Nos travaux ont permis d'identifier l’hexaréline, une molécule prototype de la famille des GHRP, comme ligand activateur du récepteur CD36. Au niveau adipocytaire, l’hexaréline favorise l’expression de gènes clés dans la régulation des acides gras suggérant un effet sur la mobilisation des acides gras par la β-oxydation et la biogenèse mitochondriale. Dans le tissu cardiaque, l’hexaréline procure des effets cardioprotecteurs mais les mécanismes impliqués restent encore peu connus. Ce travail vise à élucider le rôle de l’hexaréline et l’implication de CD36 dans la régulation de l’activité métabolique mitochondriale au niveau des cellule cardiaques. Résultats : Nous démontrons que l’activation du récepteur CD36 par l’hexaréline augmente l’activité transcriptionnelle de PPARα et module à la hausse l’expression des gènes cibles de PPARα dans les cardiomyoblastes H9C2. L’hexaréline favorise également la phosphorylation de ERK1/2 et requiert la présence de la sérine-21 du récepteur nucléaire PPARα. De plus, l’activation de CD36 augmente le potentiel transcriptionel du coactivateur PGC-1α et favorise la biogenèse mitochondriale dans les cardiomyoblastes. Conclusion : Nos travaux identifient la cascade CD36-PPARα comme élément important dans la modulation du métabolisme énergétique des cardiomyoblastes. L’activation de CD36 par l'hexaréline semble cibler de façon favorable le récepteur PPARα par la voie des MAPK/Erk, menant à l’activation transcriptionnelle de PPARα et à l'expression de gènes clés du métabolisme énergétique dans les cardiomyoblastes. Perspective : La caractérisation du rôle de la cascade métabolique CD36-PPAR va nous permettre de mieux comprendre la régulation du métabolisme énergétique au niveau cardiaque. De plus, l'identification de l'hexaréline comme modulateur bénéfique de la cascade CD36-PPAR ouvre la porte à de nouvelles possibilités d'interventions thérapeutiques pour les pathologies métaboliques., Introduction: It is known that the cellular cascade involving the scavenger receptor CD36 and the nuclear receptor PPAR has beneficial consequences on the glucolipid metabolism. Its effects on mitochondrial activity, the fatty acid oxidation process, and the hepatic reverse transport of cholesterol support the use of modulators of the CD36-PPAR cascade as potential drugs for metabolic pathologies. Our work has identified hexarelin, a prototype molecule of the GHRP family, as an activating ligand for the CD36 receptor. In adipocytes, hexarelin promotes the expression of key genes of fatty acid metabolsim, suggesting an effect on the mobilization of fatty acids for β-oxidation and mitochondrial biogenesis. In cardiac tissue, hexarelin provides cardioprotective effects, but the mechanisms involved are still poorly understood. This work aims to elucidate the role of hexarelin and the involvement of CD36 in the regulation of mitochondrial metabolic activity in cardiac cells. Methods and results: We demonstrate that activation of the CD36 receptor by hexarelin increases the transcriptional activity of PPARα and up-regulates the expression of PPARα target genes in H9C2 cardiomyoblasts. Hexarelin also promotes ERK1/2 phosphorylation and requires the presence of serine residue 21 of the nuclear receptor PPARα to achieve its tranactivation. In addition, activation of CD36 by hexarelin increases the transcriptional potential of the PGC-1α coactivator and promotes mitochondrial biogenesis in cardiomyoblasts. Conclusion: Our work identifies the CD36-PPARα cascade as an important component in the modulation of energy metabolism of cardiomyoblasts. Hexarelin activation of CD36 appears to favorably target PPARα via the MAPK / Erk pathway, leading to transcriptional activation of PPARα and upregulation of key genes of energy metabolism in cardiomyoblasts. Perspective: Characterization of the role of the CD36-PPAR metabolic cascade will allow us to better understand the regulation of energy metabolism at the cardiac level. In addition, the identification of hexarelin as a beneficial modulator of the CD36-PPAR cascade opens the door to new possibilities for therapeutic interventions for pathologies and metabolic diseases.

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the b-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual b-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced ap-optosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-kB (NF-kB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticu-lum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls b-cell sensitivity to cytokines possibly by affecting the NF-kB–inducible nitric oxide synthase– endoplasmic reticulum stress pathway., SCOPUS: ar.j, info:eu-repo/semantics/published

It is increasingly appreciated that the pathogenic mechanisms of type 1 diabetes involve both the autoimmune aggressors and their beta cell targets, which engage in a conflicting dialogue within and possibly outside the pancreas. Indeed, autoimmune CD8+ T cells, which are the final mediators of beta cell destruction, circulate at similar frequencies in type 1 diabetic and healthy individuals. Hence a universal state of ‘benign’ islet autoimmunity exists, and we hypothesise that its progression to type 1 diabetes may at least partially rely on a higher vulnerability of beta cells, which play a key, active role in disease development and/or amplification. We posit that this autoimmune vulnerability is rooted in some features of beta cell biology: the stress imposed by the high rate of production of insulin and other granule proteins, their dense vascularisation and the secretion of their products directly into the bloodstream. Gene variants that may predispose individuals to this vulnerability have been identified, e.g. MDA5, TYK2, PTPN2. They interact with environmental cues, such as viral infections, that may drive this genetic potential towards exacerbated local inflammation and progressive beta cell loss. On top of this, beta cells set up compensatory responses, such as the unfolded protein response, that become deleterious in the long term. The relative contribution of immune and beta cell drivers may vary and phenotypic subtypes (endotypes) are likely to exist. This dual view argues for the use of circulating biomarkers of both autoimmunity and beta cell stress for disease staging, and for the implementation of both immunomodulatory and beta cell-protective therapeutic strategies. [Figure not available: see fulltext.], SCOPUS: re.j, info:eu-repo/semantics/published

Fruit set is the process whereby ovaries develop into fruits after pollination and fertilization. The process is induced by the phytohormone gibberellin (GA) in tomatoes, as determined by the constitutive GA response mutant procera. However, the role of GA on the metabolic behavior in fruit-setting ovaries remains largely unknown. This study explored the biochemical mechanisms of fruit set using a network analysis of integrated transcriptome, proteome, metabolome, and enzyme activity data. Our results revealed that fruit set involves the activation of central carbon metabolism, with increased hexoses, hexose phosphates, and downstream metabolites, including intermediates and derivatives of glycolysis, the tricarboxylic acid cycle, and associated organic and amino acids. The network analysis also identified the transcriptional hub gene SlHB15A, that coordinated metabolic activation. Furthermore, a kinetic model of sucrose metabolism predicted that the sucrose cycle had high activity levels in unpollinated ovaries, whereas it was shut down when sugars rapidly accumulated in vacuoles in fruit-setting ovaries, in a time-dependent manner via tonoplastic sugar carriers. Moreover, fruit set at least partly required the activity of fructokinase, which may pull fructose out of the vacuole, and this could feed the downstream pathways. Collectively, our results indicate that GA cascades enhance sink capacities, by up-regulating central metabolic enzyme capacities at both transcriptional and posttranscriptional levels. This leads to increased sucrose uptake and carbon fluxes for the production of the constituents of biomass and energy that are essential for rapid ovary growth during the initiation of fruit set.

Context: Association of central diabetes insipidus (CDI) and pituitary stalk thickening (PST) may have several etiologies (including malignancies) and differential diagnosis remains often difficult. Objective: The purpose of this study was to identify which clinical, biochemical or radiological features could help clinicians to make an etiological diagnosis, especially distinguishing neoplastic from non-neoplastic pituitary stalk lesions. Design and methods: We retrospectively analyzed clinical, biochemical, radiological and histological data of 38 adult patients diagnosed with CDI and PST of proven etiology. Results: Of the 38 pituitary stalk lesions included, 11 (29%) were neoplastic. A histopathological diagnosis was obtained in 22/38 (58%) patients. The three most frequently observed etiologies of PST were neuroinfundibulitis (34%), germinoma (21%) and histiocytosis (18%). Pituitary stalk thickness was larger for neoplastic lesions, particularly germinomas. Male gender and a very young age were statistically associated with a risk of germinoma. At least one anterior pituitary deficit was observed in nearly 60% of patients. Patients with neoplastic PST were more affected by multiple anterior pituitary dysfunction than patients with benign PST. A high serum prolactin level was individually the best predictor of a neoplastic origin (90% sensitivity and 60% specificity for a serum prolactin level 1.27-fold above the normal upper limit (ULN)). Conclusion: We confirm a relatively high risk of malignancy in adult patients presenting with the association of CDI and PST. Young age, male gender, a very large thickening of the stalk, multiple anterior pituitary deficits and prolactin above 1.3× ULN increase the likelihood of a neoplastic origin., SCOPUS: ar.j, info:eu-repo/semantics/published

Significance Poorly irrigated tumors exhaust nutrients from their environment. On the other hand, innate immune cells, such as neutrophils and macrophages, have been frequently shown to infiltrate tumors and promote an immunosuppressive environment. Our results show that, when nutrients are low, tumor cells secrete factors related to wound healing that stimulate endothelial cells and attract innate immune cells. This suggests that targeting signals elicited by metabolic stress may help the immune system target malignant cells and that metabolites regulate the communication between immune and tumor cells also through modulation of peptidic signals., Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

International audience; Grapevine canes are an abundant byproduct of the wine industry. The stilbene contents of Vitis vinifera cultivars have been largely studied, but little is known about the stilbene contents of wild Vitis accessions. Moreover, there have only been few studies on the quantification of other phenolic compounds in just pruned grapevine canes. In our study, we investigated the polyphenol profile of 51 genotypes belonging to 15 Vitis spp. A total of 36 polyphenols (20 stilbenes, 6 flavanols, 7 flavonols, and 3 phenolic acids) were analyzed by high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer. Our results suggest that some wild Vitis accessions could be of interest in terms of the concentration of bioactive polyphenols and that flavanols contribute significantly to the antioxidant activity of grapevine cane extracts. To the best of our knowledge, this is the most exhaustive study of the polyphenolic composition of grapevine canes of wild Vitis spp.

Aims/hypothesis: High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a ‘danger signal’ (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. Methods: In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Results: Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)–Akt–mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. Conclusions/interpretation: The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes., SCOPUS: ar.j, info:eu-repo/semantics/published

Les ruminants sont des animaux sensibles, doués de capacités émotionnelles et cognitives, pouvant être soumis à différents types de douleur (excès de nociception ou neuropathique) et ceci dans différents contextes (élevage/expérimentation). L’évaluation de ces douleurs est bien souvent délicate car, pour la plupart des cas, il n’existe pas d'indicateur unique et spécifique mais plutôt un ensemble d'indicateurs dont les valeurs informatives sont souvent complémentaires. Une évaluation adéquate de la douleur est essentielle afin d'optimiser sa prise en charge et utiliser au mieux l'arsenal thérapeutique actuellement à la disposition des prescripteurs. En effet, les molécules ayant des mécanismes d’action différents, il est nécessaire de pouvoir quantifier l’intensité douloureuse et évaluer le type de douleur mis en cause. A travers cette synthèse, nous montrerons en quoi : i) l’évaluation du type et du niveau de douleur est indispensable à une prise en charge optimale de la douleur, ii) qu’une évaluation reposant sur une approche multiparamétrique est la plus adaptée à notre objectif., Ruminants are sentient beings, endowed with emotional and cognitive abilities, which can perceive different types of pain (nociceptive or neuropathic) in different types of contexts (breeding / experimentation). Assessing pain is often difficult because, in most situations of pain, there is not a unique and specific indicator but rather a set of complementary indicators. An accurate assessment of pain is essential to optimize care and use of the therapeutic arsenal currently available to prescribers. Indeed, the therapeutic arsenal with different mechanisms of action, it is necessary to quantify pain intensity and the type of pain assessment. Through this review, we will show how: i) accurate assessment is essential for optimal management of pain, ii) method of assessment depends on the type of pain that is suspected and can be based on a multiparametric approach, a limited number, or even a single indicator as appropriate.

Increased expression of transketolase (TKT) and its isoform transketolase-like-1 (TKTL1) has been related to the malignant leukemia phenotype through promoting an increase in the non-oxidative branch of the pentose phosphate pathway (PPP). Recently, it has also been described that TKTL1 can have a role in survival under hypoxic conditions and in the acquisition of radio resistance. However, TKTL1’s role in triggering metabolic reprogramming under hypoxia in leukemia cells has never been characterized. Using THP-1 AML cells, and by combining metabolomics and transcriptomics techniques, we characterized the impact of TKTL1 knockdown on the metabolic reprogramming triggered by hypoxia. Results demonstrated that TKTL1 knockdown results in a decrease in TKT, glucose-6-phosphate dehydrogenase (G6PD) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activities and impairs the hypoxia-induced overexpression of G6PD and GAPDH, all having significant impacts on the redox capacity of NADPH- and NADH-related cells. Moreover, TKTL1 knockdown impedes hypoxia-induced transcription of genes encoding key enzymes and transporters involved in glucose, PPP and amino acid metabolism, rendering cells unable to switch to enhanced glycolysis under hypoxia. Altogether, our results show that TKTL1 plays a key role in the metabolic adaptation to hypoxia in THP-1 AML cells through modulation of G6PD and GAPDH activities, both regulating glucose/glutamine consumption and the transcriptomic overexpression of key players of PPP, glucose and amino acids metabolism.

Medulloblastoma is a cancerous brain tumor that affects mostly children. It is rarely found in adults. Among the 4 groups defined according to molecular characteristics, group 3 is the least favorable with a survival rate of 50%. Current treatments, based on surgery, radiotherapy and chemotherapy, are however not sufficiently adapted to the different characteristics of the tumor, which are still not understood. In this study, we addressed the problem of medulloblastoma from a metabolic perspective in an oxygen-deficient microenvironment. Tumor hypoxia and consequent metabolism have been little studied in MB. In this study, we show that Group 3 MB have either a post-translational modificationor mutations in the PAS-A domain of HIF-1a blocking association with HIF-1b, resulting in a completely inactive HIF-1. Only HIF-2 is then present to replace HIF-1 in the activation of metabolic pathways. In vitro and in vivo data showed that pharmacological inhibitor of HIF-2a, the PT2385 , coupled with Metformin, a specific inhibitor of the mitochondrial complex I, can efficiently block and kill Group 3 MB compared to Non-Group 3 MB.We also established that cells in group 3 are more sensitive to Phenformin, a complex 1 inhibitor, than cells in other groups. Furthermore, we showed that this subgroup differentially utilizes the two shuttles, mitochondrial glycerophosphate dehydrogenase (mGPDH) and malate-aspartate shuttle (MAS), which allow NADH to move from the cytoplasm to the mitochondria. The use of phenformin and iGP1, a specific inhibitor of mGPDH, as well as the combination of the two specific inhibitors of the two shuttles, iGP1 and AOAA, clearly showed a greater ability to decrease cell proliferation and induce cell death specifically for cells in group 3 compared to cells in other groups.Our study reinforces the idea of not only molecular but also metabolic heterogeneity in the different groups that constitute medulloblastoma and provides a potential new therapeutic solution for patients in group 3 whose tumors are more aggressive., Le médulloblastome (MB) est une tumeur maligne cérébrale qui touche principalement les enfants. Elle est rarement retrouvée chez l'adulte. Parmi les 4 groupes de MB définis aujourd'hui selon des caractéristiques moléculaires, le groupe 3 est le moins favorable avec un taux de survie globale de 50 %. Les traitements actuels, basés sur la chirurgie, la radiothérapie et la chimiothérapie, ne sont pas suffisamment adaptés aux différentes caractéristiques des 4 groupes de MB.Dans ce travail de thèse, nous avons abordé le problème du médulloblastome d'un point de vue métabolique dans un micro-environnement appauvri en oxygène. L'hypoxie tumorale, et le métabolisme qui en résulte, ont été peu étudiés dans le MB. Dans cette étude, nous montrons que le groupe 3 des MB a soit une modification post-traductionnelle, soit des mutations dans le domaine PAS-A de HIF-1a bloquant l'association avec HIF-1b et entraînant un HIF-1 complètement inactif. Seul HIF-2 est alors présent pour remplacer HIF-1 dans l'activation des voies de signalisation métaboliques. Les données in vitro et in vivo ont montré que l'inhibiteur pharmacologique de HIF-2a, le PT2385, couplé à la metformine, un inhibiteur spécifique du complexe mitochondrial I, peut efficacement bloquer et tuer les cellules du groupe 3 par rapport aux autres groupes de MB.Nous avons également établi que les cellules du groupe 3 sont plus sensibles à la phenformine, un inhibiteur du complexe 1, que les cellules des autres groupes. De plus, nous avons montré que ce sous-groupe utilise différemment les deux navettes, la glycérophosphate déshydrogénase mitochondriale (mGPDH) et la navette malate-aspartate (MAS), qui permettent au NADH de se déplacer du cytoplasme vers les mitochondries. L'utilisation de phenformine et d'iGP1, un inhibiteur spécifique de mGPDH, ainsi que l'association des deux inhibiteurs spécifiques des deux navettes, iGP1 et AOAA, ont clairement montré une plus grande capacité à diminuer la prolifération cellulaire et à induire la mort cellulaire spécifiquement pour les cellules du groupe 3 par rapport aux cellules des autres groupes.Notre étude renforce l'idée d'hétérogénéité non seulement moléculaire mais aussi métabolique dans les différents groupes qui constituent le médulloblastome et apporte de nouvelles solutions thérapeutiques potentielles pour les patients du groupe 3 représentant les tumeurs les plus agressives.

Dette er den faglige sluttrapporten for prosjektet "STARTRENS – Optimalisert startfôring av rensefisk" som ble finansiert av Fiskeri- og havbruksnæringens forskningsfinansiering (#901561). Rensefisk har en sentral rolle i laksenæringen som ikke-medikamentell behandling mot lakselus, og behovet for rensefisk i laksenæringen er langt høyere enn det som oppdrettes. De første ukene av fiskeyngelens liv er avgjørende for senere suksess. Berggylt og rognkjeks er veldig forskjellige med hensyn på biologi og livshistorie, og har derfor forskjellige krav til produksjonsmetoder og dyrehold. De tidlige miljøforholdene påvirker gjerne atferd og funksjonalitet i senere stadier hos fisk, og påvirkninger i tidlige larve-stadier kan medføre langvarige endringer i vekst og fysiologiske responser. I STARTRENS har vi karakterisert eggkvalitet hos rognkjeks og berggylt med mål om å utvikle verktøy for oppdrettere som kan brukes til å velge ut de beste egg-gruppene til sine klekkeri. Vi har også brukt tidligere erfaringer med ulike levendefôr-organismer som bakgrunn for to startfôringsforsøk med rognkjeks og berggylt hvor ulike fôringsregimer ble utprøvd med mål om å optimalisere startfôringsprotokoller.

Prodrugs are drugs that have been structurally modified to produce more favorable pharmacokinetics. A common prodrug strategy involves esterification of carboxyl or hydroxyl groups to enhance drug absorption. In this paper, in vitro drug-enzyme reactions are monitored with the aim to elucidate the metabolism of novel oral antiviral molnupiravir and experimental oral remdesivir-derivative GS-621763. A method was developed using UPLC-ESI-TQ-MS/MS for simultaneous quantification of the main metabolites of both prodrugs. By incubation with recombinant human carboxylesterases, CES2 was identified as a key enzyme involved in hydrolysis of molnupiravir and GS-621763. The Michaelis constant for CES2 hydrolysis of molnupiravir was roughly estimated to be greater than 200 µM. By incubation with pooled microsomes from human livers, intestines, and lungs, GS-621763 hydrolysis is likely completed before systemic circulation.

El metabolisme embrionari s’ha relacionat amb la viabilitat embrionària, fet que suggereix el seu us per a ajudar en la selecció d’embrions d’alta qualitat en tecnologies de reproducció assistida (TRA). Malgrat els nous avenços per avaluar el metabolisme dels oòcits i embrions per determinar-ne la qualitat, encara falten mètodes per mesurar de manera no invasiva i robusta l’estat metabòlic. Fluorescence lifetime imaging microscopy (FLIM) és una tècnica d’imatge no invasiva capaç de mesurar l’estat metabòlic de les cèl·lules. FLIM mesura l’autofluorescència del dinucleòtid de nicotinamida adenina (fosfat) (NAD(P)H) i el dinucleòtid de flavina adenina (FAD+), coenzims intracel·lulars essencials per a diversos processos metabòlics. FLIM permet mesurar no només la intensitat de fluorescència d’aquestes molècules, que es correlaciona amb la seva concentració, sinó també la vida mitja dels coenzims, que proporciona informació sobre la unió enzimàtica. Una imatge de FLIM produeix 9 paràmetres quantitatius que permeten la caracterització l’estat metabòlic cel·lular. Juntament amb FLIM, també es pot obtenir second harmònic generation (SHG), una tècnica que permet l’obtenció imatges d’estructures polaritzades com el fus mitòtic. El primer estudi d’aquesta tesi te com a objectiu explorar la viabilitat, sensibilitat i seguretat de les tècniques FLIM i SHG per ser utilitzades per a l’avaluació d’oòcits i embrions de ratolí. Aquest estudi ha demostrat que FLIM en combinació amb SHG permet detectar canvis metabòlics significatius durant el desenvolupament embrionari de ratolí o canvis en l’estat metabòlic causats per pertorbacions metabòliques, sense afectar el desenvolupament embrionari. La cooperació metabòlica entre els oòcits i les cèl·lules del cúmul que l’envolten és essencial per al correcte desenvolupament d’oòcits i embrions. L’objectiu del segon estudi era determinar si FLIM podia detectar diferències en l’estat metabòlic de cèl·lules del cúmul humanes. FLIM permet mesures quantitatives de l’estat metabòlic de les cèl·lules del cúmul i detecta variacions entre diferents grups de cèl·lules del cúmul, amb una major variació entre els grups de cèl·lules de cada pacient que entre pacients. A més, hem pogut observar associacions entre els paràmetres metabòlics de les cèl·lules del cúmul i l’edat del pacient i els nivells d’hormones anti Mulleriana, però no amb l’IMC. També s’han trobat variacions entre cèl·lules del cúmul que embolcallen oòcits madurs o immadurs, indicant la possible utilització d’aquesta tècnica com a mètode d’avaluació oocitària. Els embrions de mamífer experimenten variacions en el metabolisme al llarg del seu desenvolupament preimplantacional. Aquest metabolisme s’ha relacionat amb la viabilitat embrionària, fet que suggereix el seu possible ús per a seleccionar embrions d’alta qualitat en TRA. No obstant, el metabolisme dels embrions humans encara no està completament caracteritzat, probablement a causa de la manca de mètodes no invasius per mesurar el seu estat metabòlic. El tercer estudi s’ha enfocat a determinar si la tècnica no invasiva FLIM detecta variacions en els perfils metabòlics de blastocists humans donats per recerca. S’han observat grans canvis en l’estat metabòlic en el desenvolupament en 36 hores, associats al dia des de la fecundació de l’embrió o al seu estat de desenvolupament del blastocist. Hem pogut observar una significativa heterogeneïtat metabòlica dins dels mateixos blastocists, concretament entre la massa cel·lular interna i el trofectoderm, i entre les parts de blastocists en eclosió dins i fora de la zona pel·lúcida. Aquests resultats demostren encara més que el metabolisme embrionari pre-implantacional es altament dinàmic i plàstic. En conjunt, els resultats d’aquesta tesi presenten que FLIM en combinació amb SHG pot proporcionar informació detallada i biològicament rellevant d’oòcits, embrions i cèl·lules del cúmul. Aquests nous enfocaments son prometedors per ajudar en l’avaluació de la qualitat oocitària i embrionària mitjançant mesures quantitatives no invasives del seu metabolisme i morfologia del fus mitòtic o meiòtic. El metabolismo embrionario se ha relacionado con la viabilidad embrionaria, lo que sugiere su utilización para ayudar en la selección de embriones de alta calidad en tecnologías de reproducción asistida (TRA). A pesar de nuevos avances en técnicas de evaluación el metabolismo de ovocitos y embriones para determinar su calidad, todavía faltan métodos para medir de forma no invasiva y robusta el estado metabólico. La fluorescencia lifetime imaging microscopy (FLIM) es una técnica de imagen no invasiva capaz de medir el estado metabólico celular. FLIM mide la autofluorescencia del dinucleótido de nicotinamida adenina (fosfato) (NAD(P)H) y el dinucleótido de flavina adenina (FAD+), coenzimas intracelulares esenciales para varios procesos metabólicos. FLIM permite medir la intensidad de fluorescencia de estas moléculas, que se correlaciona con su concentración, y también la vida media de las coenzimas, proporcionando información sobre la unión con enzimas. Una imagen de FLIM produce 9 parámetros cuantitativos que permiten la caracterización del estado metabólico celular. Junto con FLIM, se puede obtener second harmonic generation (SHG), una técnica que permite la obtención imágenes de estructuras polarizadas como el huso mitótico. El primer estudio de esta tesis tiene como objetivo explorar la viabilidad, sensibilidad y seguridad de las técnicas FLIM y SHG para ser utilizadas en la evaluación de ovocitos y embriones. Este estudio ha demostrado que FLIM en combinación con SHG puede detectar cambios significativos en el metabolismo durante el desarrollo embrionario de ratón o cambios causados por perturbaciones metabólicas, sin perjudicar el desarrollo embrionario. La cooperación metabólica entre los ovocitos y las células del cúmulo (CC) que le rodean es esencial para el desarrollo correcto de ovocitos y embriones. El objetivo del segundo estudio era determinar si FLIM podía detectar diferencias en el estado metabólico entre grupos de CC humanas. FLIM permite medidas cuantitativas del estado metabólico de las CC y detecta variaciones entre distintos grupos de CC, con una mayor variación entre grupos de células de cada paciente que entre pacientes. Además, hemos observado asociaciones entre los parámetros metabólicos de las CC y la edad del paciente y los niveles de hormonas anti Mulleriana, pero no con el IMC. También se han encontrado variaciones entre CC que rodean ovocitos maduros o inmaduros, indicando la posible utilización de esta técnica como método de evaluación ovocitária. Los embriones de mamífero experimentan variaciones en el metabolismo a lo largo de su desarrollo preimplantacional. Este metabolismo se ha relacionado con la viabilidad embrionaria, lo que sugiere su posible uso para seleccionar embriones de alta calidad en TRA. Sin embargo, el metabolismo de los embriones humanos todavía no está completamente caracterizado. El tercer estudio se ha enfocado a determinar si la técnica no invasiva FLIM puede detectar variaciones en los perfiles metabólicos de los blastocitos humanos donados para investigación. Hemos observado grandes cambios en el estado metabólico de los blastocitos humanos durante su desarrollo en 36 horas, cambios en el estado metabólico asociados al día desde la fecundación del embrión y a su estado de desarrollo del blastocito. Hemos podido observar una significativa heterogeneidad metabólica dentro de los propios blastocitos, concretamente entre la masa celular interna y el trofectodermo, y entre las partes de blastocitos en eclosión dentro y fuera de la zona pelúcida. Estos resultados demuestran aún más que el metabolismo embrionario preimplantacional es altamente dinámico y plástico. En conjunto, los resultados de esta tesis presentan que FLIM en combinación con SHG pueden proporcionar información detallada y biológicamente relevante de ovocitos, embriones y CC. Estos nuevos enfoques son prometedores para ayudar en la evaluación de la calidad oocitária y embrionaria mediante medidas cuantitativas no invasivas de su metabolismo y morfología del huso mitótico y meiótico. Embryo metabolism has long been linked to embryo viability, suggesting its potential utility to aid in selecting high quality embryos in assisted reproductive technologies (ART). Despite new advances to assess oocyte and embryo metabolism to determine their quality, non-invasive methods to robustly measure metabolic state are still lacking. Fluorescence lifetime imaging microscopy (FLIM) is a non-invasive method for measuring the metabolic state of cells. FLIM measures the autofluorescence of nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) and flavine adenine dinucleotide (FAD+), intracellular coenzymes essential for cellular respiration and glycolysis. FLIM enables measures of not only the fluorescence intensity of these molecules, which correlates with their concentration, but also the fluorescence lifetimes, that provides information on enzyme engagement. A metabolic measurement produces 9 quantitative parameters for characterizing the metabolic state of cells. Along with FLIM, second harmonic generation (SHG), which allows imaging of polarized structures such as the spindle, can also be obtained. The first study of this thesis aimed to explore the feasibility, sensitivity, and safety of FLIM and SHG to be used for oocyte and embryo assessment. This study showed that FLIM in combination with SHG can detect sensitively meaningful changes in metabolism through mouse embryo development. FLIM detected changes in the metabolic state due to metabolic perturbations and does not significantly impair mouse embryo development. Metabolic cooperativity between the oocytes and its surrounding cumulus cells is essential for correct oocyte and embryo development. The aim of the second study was to determine whether FLIM could detect differences in the metabolic state among human cumulus cell clusters. FLIM enabled quantitative measurements of the metabolic state of cumulus cells and detected variations between clusters, with greater variance among clusters from each patient than between patients. Additionally, cumulus cell metabolic parameters were associated with patient age and anti-Mullerian hormone levels, but not with BMI. Variations between cumulus cells associated with mature and immature oocytes were also found, suggesting the potential utility of this technique in ART assessments. Mammalian embryos undergo variations in metabolism over the course of preimplantation development. Embryo metabolism has long been linked to embryo viability, suggesting its potential use in selecting high quality embryos in ART. Nonetheless, the metabolism of human embryos is not fully characterized yet, probably due to a lack of non-invasive methods to measure their metabolic state. The third study sought to determine whether non-invasive FLIM could detect variations in metabolic profiles of human discarded blastocysts. FLIM revealed extensive changes in the metabolic state of discarded human blastocysts associated with blastocyst development over 36h, the day after fertilization and blastocyst developmental stage. Significant metabolic heterogeneity was observed within individual blastocysts, between the inner cell mass and the trophectoderm, and between the portions of hatching blastocysts within and without the zona pellucida. These results further demonstrate the highly dynamic and plastic metabolism of preimplantation embryos and the potential utility of measures of metabolic state to aid in embryo selection in ART. This thesis has sought to deepen the knowledge of non-invasive assessments of oocyte, cumulus cell and embryo metabolism. Taken together, the results of the present thesis present that FLIM in combination with SHG can provide detailed biologically relevant information and could be promising approaches to assess oocyte and embryo developmental competency through non-invasive quantitative measures of their metabolism and spindle morphology. Universitat Autònoma de Barcelona. Programa de Doctorat en Biologia Cel·lular

Bakgrunn: Selektive serotoninreopptakshemmere (SSRI) brukes av over 180 000 mennesker i Norge. Enzymene CYP2D6 og CYP2C19 er sentrale i metabolismen av SSRI-antidepressiver. Serotonintransportøren kodet av SLC6A4 kan ha betydning for effekten av medikamentene. Materiale og metode: Alle pasienter som hadde blitt genotypet for CYP2D6, CYP2C19 og SLC6A4 ved Senter for psykofarmakologi i 2020, uavhengig av indikasjon, ble inkludert. Hos de pasientene der data var tilgjengelige, ble CYP2C19-genotype koblet til serumkonsentrasjonsmåling av escitalopram, som er det mest brukte SSRI-preparatet. Resultater: 432 av 3 492 pasienter (12,4 %) hadde en kombinasjon av genotyper av CYP2D6, CYP2C19 og SLC6A4 som anses å gi mest gunstig metabolisme og effekt av SSRI-antidepressiver. Pasienter med manglende CYP2C19-metabolisme hadde mer enn halvert dosebehov for å oppnå samme konsentrasjon av escitalopram som pasienter med normal metabolisme. Fortolkning: Våre funn viser lav forekomst av den gunstigste genotypekombinasjonen for respons av SSRI-preparater. Genotypekombinasjoner bidrar sannsynligvis til den store individuelle variasjonen i effekt av disse medikamentene og til at behandlingen ikke gir ønsket utfall hos mange pasienter. Background: Selective serotonin reuptake inhibitors (SSRIs) are used by over 180,000 people in Norway. The enzymes CYP2D6 and CYP2C19 are key in the metabolism of SSRI antidepressants. The serotonin transporter coded by SLC6A4 may be significant for the efficacy of the drugs. Material and method: All patients who had undergone genotyping for CYP2D6, CYP2C19 and SLC6A4 at the Centre for Psychopharmacology in 2020 were included, irrespective of indication. For those patients where data were available, CYP2C19 genotype was linked to serum concentration measurement of escitalopram, which is the most commonly used SSRI drug. Results: Out of 3,492 patients, 432 (12.4 %) had a combination of genotypes of CYP2D6, CYP2C19 and SLC6A4 considered to lead to the most favourable metabolism and efficacy of SSRI antidepressants. The dose requirement in patients with poor CYP2C19 metabolism was more than halved to achieve the same concentration of escitalopram compared to patients with normal metabolism. Interpretation: Our findings demonstrate the low prevalence of the most favourable genotype combination for response to SSRIs. Genotype combinations probably contribute to the wide variation between individuals in the efficacy of these drugs and the fact that treatment does not produce the desired outcome in many patients.

Altres ajuts: acords transformatius de la UAB Altres ajuts: Social Sciences and Humanities Research Council of Canada (SFS 895-2011-1020) Altres ajuts: Pontificia Universidad Javeriana de Cali (SIGI 275) Current agricultural systems have reached a critical transition point in their biophysical performance, social and environmental impacts, and energy patterns. The theoretical underpinnings of transitions towards sustainable futures have been studied from different approaches. The perspective of Social Metabolism (SM) studies how dynamic equilibriums of society-nature interactions arise in complex agroecosystems characterized by specific metabolic profiles that set their capabilities and limits. Changes between these regimes are understood as sociometabolic Transitions (SMT).This article offers a quantitative and qualitative review of how these SM and SMTs have been studied in Latin America so far, pointing out: i) the main conceptual and methodological approaches used, ii) the geographical scales of analysis, and iii) the main periods studied in the literature review. After identifying the different ways to account for the SMTs in LA, it discusses the prevailing SM narratives on the region's economic development. We found a scarce effort in carrying out multi-scalar studies linking national data with local case studies and a need to spread and adopt innovative SM methodologies and indicators to carry out more complex and comprehensive research on how inequality has framed the LA's agricultural paths and set their prospects.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula. The project leading to these results received funding from the La Caixa Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 to IF; it was also supported by the Ministry of Economy and Competitiveness, Institute of Health Carlos III (ISCIII) (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FISPI17/000809 to IF; and the IntraCIBERNED 2019 collaborative project to IF and JADR. This work was also co-financed by ERDF under the program Interreg Poctefa: RedPrion 148/16; ERDF [148/16]. We thank CERCA Programme/Generalitat de Catalunya for institutional support.

Les malalties no transmissibles, com l'obesitat, la síndrome metabòlica, les malalties cardiovasculars, el càncer i les malalties neurodegeneratives, es consideren malalties multifactorials. Per aquesta raó, s'ha proposat que l'aparició d’aquestes malalties es deu a un desequilibri de processos globals. El seguiment d'aquests processos obre la porta a la possibilitat de modular-los i, per tant, prevenir-los mitjançant el disseny d'intervencions/tractaments personalitzats més precisos. No obstant això, els biomarcadors actuals no tenen la capacitat d'avaluar les alteracions primerenques que podrien conduir al desenvolupament de la malaltia, la qual cosa posa de manifest la necessitat de definir nous biomarcadors. Per tant, en el present treball es presenta una signatura metabòlica característica de processos específics obtinguda mitjançant l'ús de tecnologies òmiques: disfunció de carbohidrats, hiperlipèmia, hipertensió i dysbiosis intestinal, com a representatius de l'estrès metabòlic; l'estrès inflamatori; l'estrès oxidatiu i l'estrès psicològic. Per això, s'han desenvolupat diferents models animals i s'ha avaluat el perfil metabòlic dels diferents factors de risc d'interès en plasma i orina. Els resultats indiquen que els lípids i els intermediaris del cicle del TCA són els metabòlits més prometedors del perfil metabòlic. En tots els factors de risc, els diacilglicerols (DG) són els biomarcadors lipídics amb major impacte: en concret, el DG 36:4 i el DG 34:2 vinculen els factors de risc amb el metabolisme de l'àcid araquidònic. En inflamació, estrès oxidatiu i psicològic, l'altre protagonista és el cicle del TCA a causa del seu paper clau en el mitocondri amb l'alfa-cetoglutarat com l'intermediari més prometedor. En conseqüència, el perfil metabòlic presentat és una eina potencial per al seguiment dels factors de risc i podria obrir una finestra per a orientar l'aparició de malalties i intentar prevenir-les i tractar-les. Las enfermedades no transmisibles, como la obesidad, el síndrome metabólico, las enfermedades cardiovasculares, el cáncer y las enfermedades neurodegenerativas, se consideran enfermedades multifactoriales. Por esta razón, se ha propuesto que la aparición de estas enfermedades se debe a un desequilibrio de procesos globales. El seguimiento de estos procesos abre la puerta a la posibilidad de modularlos y, por lo tanto, prevenirlos mediante el diseño de intervenciones/tratamientos personalizados más precisos. Sin embargo, los biomarcadores actuales no tienen la capacidad de evaluar las alteraciones tempranas que podrían conducir al desarrollo de la enfermedad, lo que pone de manifiesto la necesidad de definir nuevos biomarcadores. Por lo tanto, en el presente trabajo se presenta una firma metabólica característica de procesos específicos obtenida mediante el uso de tecnologías ómicas: disfunción de carbohidratos, hiperlipidemia, hipertensión y disbiosis intestinal, como representativos del estrés metabólico; el estrés inflamatorio; el estrés oxidativo y el estrés psicológico. Para ello se han desarrollado diferentes modelos animales y se ha evaluado el perfil metabólico de los diferentes factores de riesgo de interés en plasma y orina. Los resultados indicaron que los lípidos y los intermediarios del ciclo del TCA son los metabolitos más prometedores del perfil metabólico. En todos los factores de riesgo, los diacilgliceroles (DG) son el biomarcador lipídico con mayor impacto: en concreto, el DG 36:4 y el DG 34:2 vinculan los factores de riesgo con el metabolismo del ácido araquidónico. En inflamación, estrés oxidativo y psicológico, el otro protagonista es el ciclo del TCA debido a su papel clave en la mitocondria con el alfa-cetoglutarato como el intermediario más prometedor. En consecuencia, el perfil metabólico presentado es una herramienta potencial para el seguimiento de los factores de riesgo y podría abrir una ventana para orientar la aparición de enfermedades e intentar prevenirlas y tratarlas. Non-communicable diseases, such as obesity, metabolic syndrome, cardiovascular diseases, cancer and neurodegenerative diseases, are considered multifactorial diseases. For this reason, it has been proposed that the occurrence of these diseases is due to an imbalance of overarching processes (i.e., metabolic, inflammatory, oxidative, and psychological stress). Monitoring these overarching processes opens the door to the possibility of modulating them, and thus preventing the occurrence of different process through the design of more precise personalised interventions or treatments. However, current biomarkers of disease cannot assess early alterations that could lead to the development of disease, highlighting the need to define new biomarkers. Thus, the present work presents a characteristic metabolic signature for the detection of specific processes using omic technologies: carbohydrate dysfunction, hyperlipidaemia, hypertension and intestinal dysbiosis, as representative of metabolic stress; inflammatory stress; oxidative stress and psychological stress. For this purpose, different animal models have been developed and the metabolic profile in plasma and urine has been evaluated in the different risk factors of interest. The results indicated that lipids and TCA cycle intermediates are the most promising metabolites of the metabolic profile. In all the risk factors, diacylglycerols (DG) are the lipidic biomarker with the greatest impact on metabolic profiles: specifically, DG 36:4 and DG 34:2 linking risk factors to arachidonic acid metabolism. In inflammation, oxidative and psychological stress, the other protagonist is the TCA cycle due to its multiple roles in mitochondrial metabolism: being alpha-ketoglutarate one of the most promising intermediate. In consequence, the presented metabolic profile is a potential tool for the monitoring of risk factors and could open a window to target the onset of diseases and try to prevent and treat them.

Els carotenoides són compostos isoprenoides essencials per a la fotosíntesi, la fotoprotecció, i com a precursors de reguladors del creixement com l'àcid abscísic (ABA) i les estrigolactones (SL). En algunes plantes, com el tomàquet (Solanum lycopersicum), els carotenoides també funcionen com a pigments que donen color a les flors i als fruits per atraure pol·linitzadors i als animals dispersors de llavors. Els carotenoides deriven del precursor geranil geranil difosfat (GGPP), sintetitzat als plasts per les GGPP sintases (GGPPS). Dues molècules de GGPP són després condensades per les fitoè sintases (PSY) per produir fitoè, el primer intermediari de la ruta dels carotenoides. Tot i que les GGPPS i PSY s'han estudiat àmpliament a Arabidopsis, el nostre coneixement de les famílies gèniques i la seva regulació a la majoria dels cultius, inclòs el tomàquet, és limitat. A Arabidopsis, només hi ha una isoforma de GGPPS què és essencial als plasts, on es capaç d'interaccionar amb l'única PSY present en aquesta espècie model. Tot i això, en tomàquet, hi ha tres gens que codifiquen isoformes de GGPPS (SlG1-3) i tres per a les isoformes de PSY (PSY1-3). L'objectiu principal d'aquesta tesi ha estat compendre millor la contribució específica de les isoformes GGPPS i PSY a la producció de carotenoides en diferents teixits de la planta de tomàquet. Per això, s'ha organitzat el treball en dos blocs principals: (1) identificar i caracteritzar els membres plastidials de la família GGPPS de tomàquet, i (2) confirmar i explorar els rols de les isoformes PSY. Utilitzem la tecnologia CRISPR-Cas9 per generar mutants de tomàquet defectius a les tres isoformes GGPPS i en dues de les isoformes PSY per assolir els nostres objectius. Descobrim que SlG3 funciona com a isoforma "housekeeping", proporcionant la major part del GGPP necessari per produir isoprenoides fotosintètics en fulles i carotenoides en fruit, no obstant l'expressió de SlG2 s'activa en els moments de més demanda de carotenoides per ajudar amb GGPP extra. Curiosament, l'absència de SlG2 i SlG3 produeix fenotips letals durant el desenvolupament de la llavor. A més, descobrim que el paper de SlG1 es restringeix principalment a les arrels, on produeix GGPP per a la síntesi d'estrigolactones, i és incapaç de compensar la pèrdua de SlG2 i SlG3. Referint-nos a la família de PSY, les nostres dades indiquen que PSY2 és la principal isoforma productora de carotenoides als teixits fotosintètics, mentre que PSY1 funciona principalment en els cromoplasts de flors i fruits. A més, hem descobert un paper de PSY1 als teixits fotosintètics quan les plantes estan exposades a alta llum. A més, descobrim un rol per a aquestes isoformes a la producció d'ABA en diferents teixits del fruit. En particular, hem observat que PSY1 proporciona fitoè per a la síntesi d'ABA al pericarp, mentre que PSY2 té un paper a l'ABA de llavor, en el control de la germinació. A més, la pèrdua conjunta de les dues isoformes dona lloc a un fenotip albí letal, quelcom indica que PSY3 no és activa en els teixits fotosintètics durant el desenvolupament i que la seva funció es limita principalment a les arrels. Finalment, els nostres experiments de co-immunoprecipitació proteica han revelat interaccions específiques entre els membres de les famílies GGPPS-PSY: mentre SlG1 interactua amb PSY3, SlG2 ho fa amb PSY1 i PSY2, i curiosament, SlG3 no interactua amb cap PSY. Amb aquestes dades, concluim, que el parell SlG1-PSY3 és l'encarregat del subministrament de precursors per a la síntesi de SL a les arrels, mentre que els parells SlG2-PSY2 i SlG2-PSY1 canalitzen la producció de GGPP cap a la síntesi de carotenoides i ABA a la part aèria de la planta de tomàquet. Los carotenoides son compuestos isoprenoides esenciales para la fotosíntesis, la fotoprotección, y como precursores de reguladores del crecimiento como el ácido abscísico (ABA) y las estrigolactonas (SL). En algunas plantas, como el tomate (Solanum lycopersicum), los carotenoides también funcionan como pigmentos que dan color a las flores y a los frutos para atraer a polinizadores y a los animales dispersores de semillas. Los carotenoides derivan del precursor geranil geranil difosfato (GGPP), sintetizado en los plastos por las GGPP sintasas (GGPPS). Dos moléculas de GGPP son después condensadas por las fitoeno sintasas (PSY) para producir fitoeno, el primer intermediario de la ruta de los carotenoides. Aunque las GGPPS y PSY se han estudiado ampliamente en Arabidopsis, nuestro conocimiento de las familias génicas y su regulación en la mayoría de los cultivos, incluido el tomate, es pequeño. En Arabidopsis, sólo una isoforma de GGPPS es esencial en los plastos, donde, además es capaz de interaccionar con la única PSY presente en esta especie. Sin embargo, en tomate, hay tres genes que codifican isoformas de GGPPS (SlG1-3) y tres para las isoformas de PSY (PSY1-3). El objetivo principal de esta tesis ha sido entender mejor la contribución específica de las isoformas GGPPS y PSY en la producción de carotenoides en diferentes tejidos de la planta de tomate. Para ello, organizamos el trabajo en dos bloques principales: (1) identificar y caracterizar los miembros plastidiales de la familia GGPPS de tomate, y (2) confirmar y explorar los roles de las isoformas PSY. Utilizamos la tecnología CRISPR-Cas9 para generar mutantes de tomate defectivos en las tres isoformas GGPPS y en dos de las isoformas PSY para alcanzar nuestros objetivos. Descubrimos que SlG3 funciona como isoforma "housekeeping", proporcionando la mayor parte del GGPP necesario para producir isoprenoides fotosintéticos en hojas y carotenoides en fruto, mientras que la expresión de SlG2 se activa en los momentos de mayor demanda de carotenoides para ayudar con GGPP extra. Curiosamente, la ausencia de SlG2 y de SlG3 produce fenotipos letales durante el desarrollo de la semilla. Además, descubrimos que el papel de SlG1 se restringe principalmente a las raíces, donde produce GGPP para la síntesis de estrigolactonas, y es incapaz de compensar la pérdida de SlG2 y SlG3. Respecto a la familia de PSY, nuestros datos indican que PSY2 es la principal isoforma productora de carotenoides en los tejidos fotosintéticos, mientras que PSY1 funciona principalmente en los cromoplastos de flores y frutos. Además, hemos descubierto un papel de PSY1 en los tejidos fotosintéticos cuando las plantas están expuestas a alta luz. Además, descubrimos un rol para estas isoformas en la producción de ABA en diferentes tejidos del fruto. En particular, observamos que PSY1 proporciona fitoeno para la síntesis de ABA en el pericarpo, mientras que PSY2 tiene un papel en el ABA de semilla, en control de la germinación. Además, la pérdida conjunta de ambas isoformas da lugar a un fenotipo albino letal, lo que indica que PSY3 no es activa en los tejidos fotosintéticos durante el desarrollo y que su función se limita principalmente a las raíces. Finalmente, nuestros experimentos de co-inmunoprecipitación proteica, han revelado interacciones específicas entre los miembros de las familias GGPPS-PSY: mientras SlG1 interactúa con PSY3, SlG2 lo hace con PSY1 y PSY2, y curiosamente, SlG3 no interactúa con ninguna PSY. Con esos datos, concluimos, que el dúo SlG1-PSY3 es el encargado del suministro de precursores para la síntesis de SL en las raíces, mientras que los pares SlG2-PSY2 y SlG2-PSY1 canalizan la producción de GGPP hacia la síntesis de carotenoides y ABA en la parte aérea de la planta de tomate. Carotenoids are isoprenoid compounds essential for photosynthesis and photoprotection but also as precursors of growth regulators such as abscisic acid (ABA) and strigolactones (SLs). In some plants, including tomato (Solanum lycopersicum), carotenoids also function as pigments that provide color to flowers and ripe fruit to attract animals for pollination and seed dispersion. Carotenoids are derived from plastidial geranylgeranyl diphosphate (GGPP) synthetized by GGPP synthases (GGPPS). Two molecules of GGPP are condensed by phytoene synthases (PSY) to produce phytoene, the first committed intermediate of the carotenoid pathway. Combined activity of GGPPS and PSY enzymes channel the production of GGPP towards carotenoids and away from other downstream plastidial isoprenoids that also derive from GGPP (e.g. chlorophylls, tocopherols, plastoquinone, or gibberellins). Although GGPPS and PSY have been broadly studied in Arabidopsis, less is known about the gene families encoding these enzymes and their regulation in most crops, including tomato. In Arabidopsis, only one GGPPS isoform is essential in plastids, where it interacts with the only PSY enzyme present in this species. In tomato, however, there are three genes encoding GGPPS isoforms (herein named SlG1 to 3) and three for PSY isoforms (PSY1 to 3). The main objective of this thesis was to better understand the contribution of specific GGPPS and PSY isoforms for the production of carotenoids in different tissues of the tomato plant, with a particular interest in deciphering the relevance of coordinated expression profiles and direct protein-protein interactions for the channeling of GGPP into the carotenoid pathway. To this end, the work was organized in two main blocks: (1) to identify and characterize the plastidial members of the tomato GGPPS family, and (2) to confirm and explore functional roles for tomato PSY isoforms. We used CRISPR-Cas9 editing to generate tomato mutants defective in all three GGPPS isoforms and two PSY isoforms as the main tools to achieve our objectives. We found that SlG3 acts as a housekeeping GGPPS isoform providing most of the GGPP necessary to produce photosynthesis-related isoprenoids and fruit carotenoids, whereas SlG2 is upregulated during peak-demands of carotenoids to help in delivering GGPP substrates. Intriguingly, absence of both SlG2 and SlG3 results in lethal seed/embryo phenotypes. The role of SlG1 is mainly restricted to roots, where it produces GGPP for the synthesis of carotenoid-derived hormone SLs. As for the PSY family, our results confirmed that PSY2 is the main isoform producing carotenoids in photosynthetic tissues whereas PSY1 functions mainly in flower and fruit chromoplasts. They also unveiled a supporting role for PSY1 in chloroplasts when plants are exposed to high light. A specific role for each of these isoforms in the production of ABA was found in different fruit tissues. In particular, PSY1 provides carotenoid precursors for ABA synthesis in the pericarp to regulate fruit growth and ripening whereas PSY2 acts in the seed and modulates ABA production to regulate germination. Loss of both PSY1 and PSY2 isoforms results in an albino seedling-lethal phenotype, indicating that PSY3 is not active in photosynthetic shoot tissues but its role is mainly restricted to roots. Co-immunoprecipitation experiments showed specific GGPPS-PSY interactions: SlG1 only interacts with PSY3, SlG2 with PSY1 and PSY2, and SlG3 does not interact with any PSY isoform. We therefore conclude that the SlG1-PSY3 pair ensures the supply of precursors for SL and other carotenoid-derived products in roots, whereas SlG2-PSY2 and SlG2-PSY1 pairs might efficiently channel GGPP production to the synthesis of carotenoids and ABA in shoot tissues. All the new information generated here will be very useful to further design strategies for crop enrichment in carotenoids and other health-promoting GGPP-derived metabolites of specific tissues or under challenging climate conditions.

Les galopeurs sont capables de courir à plus de 60 km/h sur des distances allant de 900 à 4 000 m pour les courses de plat et de 2 800 à 7 300 m pour les courses d’obstacles. Afin de réaliser de tels efforts, l’approvisionnement en énergie recourt à différentes voies métaboliques dont la contribution dépend de l’intensité et de la durée de l’effort. Une étude de terrain, incluant 11 galopeurs Pur-sang, a été réalisée afin d’évaluer l’implication du métabolisme lipidique lors d’une séance d’entraînement et de déterminer quels marqueurs seraient potentiellement utiles au suivi de l’entraînement. Les analyses biochimiques classiques confirment l’implication du métabolisme lipidique dans l’apport énergétique lors de l’exercice chez le galopeur. Cependant, les informations relatives à leur métabolisation restent limitées. Le recours à de nouveaux marqueurs, tel que le profil en acylcarnitines, apparaît comme un outil intéressant pour investiguer le métabolisme énergétique. Outre l’acquisition de nouvelles connaissances relatives à l’implication des différentes voies métaboliques au cours de l’effort, la détermination du profil des acylcarnitines pourrait s’avérer utile au suivi médicosportif du galopeur.

Peer reviewed: True, Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.